Prozac
Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac).

Garcia-Colunga J, Awad JN, Miledi R.

Department of Psychobiology, University of California, Irvine 92697-4550, USA.

Fluoxetine (Prozac), a widely used antidepressant, is said to exert its medicinal effects almost exclusively by blocking the serotonin uptake systems. The present study shows that both muscle and neuronal nicotinic acetylcholine receptors are blocked, in a noncompetitive and voltage-dependent way, by fluoxetine, which also increases the rate of desensitization of the nicotinic receptors. Because these receptors are very widely distributed in the both central and peripheral nervous systems, the blocking action of fluoxetine on nicotinic receptors may play an important role in its antidepressant and other therapeutical effects. Our findings will help to understand the mode of action of fluoxetine, and they may also help to develop more specific medicinal drugs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9050901&dopt=Abstract fluoxetine Prozac



Prozac
Cost-effectiveness of newer antidepressants compared with tricyclic antidepressants in managed care settings.

Revicki DA, Brown RE, Keller MB, Gonzales J, Culpepper L, Hales RE.

MEDTAP International, Bethesda, Md. 20814, USA.

BACKGROUND: Our aim was to determine the cost-effectiveness of newer antidepressants compared with tricyclic antidepressants in managed care organization settings. METHOD: We employed cost-utility analysis based on a clinical decision analysis model derived from published medical literature and physician judgment. The model, which represents ideal primary care practice, compares treatment with nefazodone to treatment with either imipramine or fluoxetine or to a step approach involving initial treatment with imipramine followed by nefazodone for treatment failures. The outcome measures were lifetime medical costs, quality-adjusted life years (QALYs), and costs per QALY gained. RESULTS: The base case analysis found that nefazodone treatment had $16,669 in medical costs, compared with $15,348 for imipramine, $16,061 for the imipramine step approach, and $16,998 for fluoxetine. QALYs were greatest for nefazodone (14.64), compared with 14.32 for imipramine, 14.40 for the step approach, and 14.58 for fluoxetine. The cost-effectiveness ratio comparing nefazodone with imipramine was $4065 per QALY gained. The cost-effectiveness ratio comparing nefazodone with the step approach was $2555 per QALY gained. There were only minor differences in costs and outcomes between nefazodone and fluoxetine, with nefazodone resulting in $329 fewer costs and 0.06 more QALYs. The cost-effectiveness ratios comparing fluoxetine with imipramine and with the step approach were $6346 per QALY gained and $5206 per QALY gained, respectively. In the sensitivity analyses, the cost-effectiveness ratios comparing nefazodone and imipramine ranged from $2572 to $5841 per QALY gained. The model was most sensitive to assumptions about treatment compliance rates. CONCLUSION: The findings suggest that nefazodone is a cost- effective treatment compared with imipramine or fluoxetine treatment for major depression. Fluoxetine is cost-effective compared with imipramine treatment, but is estimated to have slightly more medical costs and less effectiveness compared with nefazodone. The basic findings and conclusions do not change even after modifying key model parameters.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9062373&dopt=Abstract fluoxetine Prozac



Prozac
Dopaminergic and serotonergic properties of fluoxetine.

Simon B, Appel JB.

Department of Psychology, University of South Carolina, Columbia, USA.

1. Rats were trained to discriminate i.p. injections of a 5-HT agonist, LSD (0.08 mg/kg, n = 12) or a DA agonist, cocaine (10 mg/kg; n = 16) in a two lever, drug discrimination situation. 2. Animals were tested with fluoxetine (0.625-10 mg/kg) alone and in combination with low doses of the training drugs. 3. Fluoxetine did not substitute for either LSD or cocaine at any dose tested. A relatively low dose of fluoxetine (2.5 mg/kg) potentiated the discriminability of cocaine (2.5 mg/kg) from saline. A higher dose of fluoxetine (5.0 mg/kg) significantly enhanced the effects of a low dose of LSD (0.02 mg/kg), but only to 41.7% responses on the LSD-appropriate lever. 4. The data suggest that fluoxetine alters the discriminative stimulus properties of cocaine to a greater extent than those of LSD. 5. The ability of fluoxetine to potentiate the cocaine cue (but not to substitute for cocaine) suggests that both of those drugs affect DA systems, but do so through different mechanisms. For example, fluoxetine may not inhibit DA reuptake (to the same extent as cocaine), but may have other dopaminergic actions such as increasing DA receptor density.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9075265&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine selectively alters 5-hydroxytryptamine1A and gamma-aminobutyric acidB receptor-mediated hyperpolarization in area CA1, but not area CA3, hippocampal pyramidal cells.

Beck SG, Birnstiel S, Choi KC, Pouliot WA.

Department of Pharmacology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153, USA.

Fluoxetine is a 5-hydroxytryptamine (5-HT, serotonin)-selective reuptake inhibitor (SSRI) and is one of the main drugs used for the treatment of depression. Because it takes 2 to 3 weeks of treatment before clinical efficacy is manifest, the acute actions of fluoxetine cannot account for the clinical actions of the drug. The chronic effects of fluoxetine have not been completely delineated. The experiments detailed here investigate the chronic effects of fluoxetine on 5-HT and gamma-aminobutyric acid (GABA) receptor-mediated actions using intracellular recording techniques in hippocampal brain slices. Rats were treated with fluoxetine for 3 weeks via osmotic minipumps implanted s.c. Fluoxetine and norfluoxetine plasma levels were determined. The hippocampal pyramidal cell characteristics and the 5-HT1A and GABA(B) receptor-mediated hyperpolarization were measured in the CA1 and the CA3 subfields. The 5-HT4 receptor-mediated decrease in the slow afterhyperpolarization amplitude was also recorded in area CA1. The time constant, magnitude of the change in resistance during 300-ms hyperpolarizing current pulses and half-decay time of the sAHP were altered by chronic fluoxetine treatment in area CA1 pyramidal cells. No changes were seen in any of the active or passive membrane properties of the CA3 hippocampal pyramidal cells. Fluoxetine treatment increased the potency of 5-HT for the 5-HT1A receptor-mediated hyperpolarization in area CA1, but not area CA3, and decreased the potency of baclofen for the GABA(B) receptor-mediated hyperpolarization in area CA1, but not area CA3. The characteristics of the concentration-response curve for the 5-HT-mediated decrease in sAHP amplitude in area CA1 were not altered by fluoxetine treatment. Chronic fluoxetine selectively and differentially altered the cell characteristics and the 5-HT1A and GABA(B) receptor-mediated responses in area CA1 of the hippocampus, which forms the final common output of the hippocampus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9103487&dopt=Abstract fluoxetine Prozac



Prozac
Electrophysiological effects of fluoxetine and duloxetine in the dorsal raphe nucleus and hippocampus.

Smith JE, Lakoski JM.

Department of Pharmacology, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine, Hershey 17033, USA.

The cellular electrophysiological effects of duloxetine (LY248686), a dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine reuptake inhibitor, and the selective serotonin reuptake inhibitor fluoxetine were compared on spontaneously active neurons in the dorsal raphe nucleus and the hippocampus of chloral hydrate-anesthetized male rat. Systemic intravenous administration of duloxetine or fluoxetine inhibited dorsal raphe nucleus cell firing in a dose-dependent manner; duloxetine suppressed cell firing at significantly lower doses (ED100 1.4 +/- 0.3 mg/kg) than fluoxetine (ED100 10.0 +/- 2.0 mg/kg). In the hippocampus, microiontophoretic application of duloxetine or fluoxetine (0.01 M, pH 5.5; 5-40 nA) produced minimal inhibition of cell firing. When duloxetine was co-applied with 5-HT, the recovery response (RT50 values) of hippocampal pyramidal neurons to 5-HT application was not altered. In contrast, co-application of fluoxetine with 5-HT at the same iontophoretic currents significantly increased (59%) the RT50 values produced by 5-HT application alone. This physiological and pharmacological study contributes to understanding the cellular mechanisms of these agents which may be useful in the treatment of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9105878&dopt=Abstract fluoxetine Prozac



Prozac
Anxiolytic and memory improving activity of fluoxetine.

Nowakowska E, Chodera A, Kus K.

Department of Pharmacology, Medical Academy, Poznan, Poland.

The anxiolytic and memory improving effects of fluoxetine, a new antidepressant drug, were investigated in rats. Anxiolytic activity was examined using Crowley's "two compartment exploratory test". Memory was assayed in the response passive avoidance test (RPAT) and labyrinth test. Wistar rats were used in all experiments. They were given fluoxetine hydrochloride (5 mg/kg po) and scopolamine hydrobromide at the dose of 0.5 mg/kg, sc. It was found that the drug has a high anxiolytic activity after the first administration. Thereafter however, the anxiolytic effect gradually decreased and 28 days later it was no longer present. In memory testing experiments (RPAT and labyrinth test) fluoxetine improved the performance of memory task and up to 14 days there were no signs of tolerance development. The authors discuss the possibility of involvement of the anxiolytic and memory improving effects of fluoxetine in the antidepressant action of the drug.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9112660&dopt=Abstract fluoxetine Prozac



Prozac
Essentiality of central GABAergic neuroactive steroid allopregnanolone for anticonvulsant action of fluoxetine against pentylenetetrazole-induced seizures in mice.

Ugale RR, Mittal N, Hirani K, Chopde CT.

University Department of Pharmaceutical Sciences, Nagpur University Campus, Nagpur 440 033, Maharashtra, India.

Fluoxetine, a selective serotonin reuptake inhibitor, is known to increase the cortical content of allopregnanolone (ALLO) without altering the level of other neurosteroids. In contrast to the proconvulsant effect of many antidepressants, fluoxetine exhibits anticonvulsant effects. The present study was undertaken to examine the role of ALLO in the anticonvulsant action of fluoxetine against pentylenetetrazole (PTZ)-induced seizures in mice. Prior administration of GABA(A) receptor agonist muscimol or neurosteroid ALLO or progesterone, a precursor of ALLO or neurosteroidogenic drugs like FGIN 1-27, an agonist at the mitochondrial diazepam binding inhibitor receptor (MDR) or metyrapone, an 11beta-hydroxylase inhibitor, significantly potentiated the anticonvulsant effect of fluoxetine. In contrast, the effect of fluoxetine was counteracted by inhibition of the neurosteroid biosynthesis using drugs like 5alpha-reductase inhibitor, finasteride; 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane; 3alpha-hydroxysteroid dehydrogenase inhibitor, indomethacin; MDR antagonist, PK 11195; or the GABA(A) receptor antagonist, bicuculline. Further, bilateral adrenalectomy had no significant effect on the anticonvulsant action of fluoxetine, suggesting negligible contribution from peripheral steroidogenesis. The anticonvulsant effect of fluoxetine was partially abolished in 5,7-DHT treated mice, indicating that the effect may also, in part, be dependent on serotonergic transmission. Thus, our data indicate that increased synthesis of ALLO in CNS is a major factor that ultimately leads to anticonvulsant effects of fluoxetine against PTZ-induced seizures.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15364024&dopt=Abstract fluoxetine Prozac



Prozac
In vitro adsorption study of fluoxetine onto activated charcoal at gastric and intestinal pH using high performance liquid chromatography with fluorescence detector.

Tsitoura A, Atta-Politou J, Koupparis MA.

University of Athens, Greece.

BACKGROUND: This in vitro investigation was performed to study the adsorption characteristics of fluoxetine to activated charcoal and its commercial formulation Carbomix powder in simulated gastric (pH = 1.2) and intestinal (pH = 7.2) fluid environments. METHODS: Solutions containing fluoxetine and charcoal were incubated at 37 degrees C for one hour. Reversed phase high performance liquid chromatography was used for the determination of free fluoxetine concentrations (range 0.2-8 micrograms/mL) in the diluted filtrate. RESULTS: The maximum adsorption capacities at pH 1.2 for activated charcoal and Carbomix were 223 and 333 mg/g, respectively; at pH 7.2 they were 301 and 453 mg/g, respectively. The affinity constant values at pH 1.2 of activated charcoal and Carbomix were 441 and 122 L/g, respectively, while at pH 7.2 they were 482 and 589 L/g, respectively, indicating a strong binding of fluoxetine onto charcoals. CONCLUSIONS: Relative to the toxic and lethal doses in cases of fluoxetine intoxications, both types of charcoals tested were found effective for adsorption at gastric and intestinal pH. Adsorbed fluoxetine was significantly increased at intestinal pH, consistent with predominant adsorption of the undissociated form of the drug. We conclude that activated charcoal and Carbomix have adsorptive properties appropriate to medical treatment in cases of fluoxetine overdose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9140321&dopt=Abstract fluoxetine Prozac